Abstract
In addition to its antimicrobial activity, the skin-derived antimicrobial peptide human β-defensin-3 (hBD-3) promotes keratinocyte proliferation and migration to initiate the wound healing process; however, its effects on fibroblasts, which are the major cell type responsible for wound healing, remain unclear. We investigated the role of hBD-3 in cell migration, proliferation and production of angiogenic growth factors in human fibroblasts and evaluated the in vivo effect of hBD-3 on promoting wound healing and angiogenesis. Following hBD-3 treatment, the mouse wounds healed faster and showed accumulation of neutrophils and macrophages in the early phase of wound healing and reduction of these phagocytes 4 days later. hBD-3-treated wounds also displayed an increased number of fibroblasts and newly formed vessels compared to those of the control mice. Furthermore, the expression of various angiogenic growth factors was increased in the hBD-3-treated wounds. Additionally, in vitro studies demonstrated that hBD-3 enhanced the secretion of angiogenic growth factors such as fibroblast growth factor, platelet-derived growth factor and vascular endothelial growth factor and induced the migration and proliferation of human fibroblasts. The hBD-3-mediated activation of fibroblasts involves the fibroblast growth factor receptor 1 (FGFR1)/Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathways, as evidenced by the inhibitory effects of pathway-specific inhibitors. We indeed confirmed that hBD-3 enhanced the phosphorylation of FGFR1, JAK2 and STAT3. Collectively, the current study provides novel evidence that hBD-3 might be a potential candidate for the treatment of wounds through its ability to promote wound healing, angiogenesis and fibroblast activation.
Highlights
The skin is the most external organ that protects the body from physical and chemical environmental challenges
Previous studies showed that the skin-derived antimicrobial peptide human bdefensin-3 (hBD-3) chemoattracts macrophages, mast cells and keratinocytes that contribute to the wound healing process [19, 39]; the effects of human b-defensins (hBDs)-3 on fibroblasts have not been reported far
In vitro studies demonstrated that hBD-3 enhanced the production of various angiogenic growth factors and induced the migration and proliferation of human fibroblasts through the fibroblast growth factor receptor 1 (FGFR1)/JAK2/signal transducer and activator of transcription 3 (STAT3) pathways (Figure 9)
Summary
The skin is the most external organ that protects the body from physical and chemical environmental challenges. The skin wound healing process consists of three distinct but overlapping stages, denoted as the inflammatory phase, proliferative phase, and remodeling phase, and involves several mediators, such as inflammatory cells, growth factors and cellular and extracellular elements [1]. Both neutrophils and macrophages are attracted to the wound site to ingest and kill microbes, remove damaged tissues and release proinflammatory cytokines and growth factors that recruit and activate fibroblasts and keratinocytes. Keratinocytes and fibroblasts proliferate and migrate to the wound site, where fibroblasts synthesize extracellular matrix (ECM) to form granulation tissues. In this phase, angiogenesis plays an important role by supplying newly formed tissue. In addition to the ECM, MMPs cleave many cytokines, growth factors and cytokine/growth factor receptors that regulate several steps of the wound healing process [2]
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